Esters of quaternary z-hydroxy methyl
piperidinium compounds



United States Patent 3 240 784 ESTERS OF UATERNARi! Z-HYDROXY METHYLPIPERIDINIUM COMPOUNDS Kurt Flick, Stolberg, Rhineland, and HeinrichMueckter,

Aachen, Rhineland, Germany, assignors, by mesne assignments, to the firmProtochemie AG, Glarus, Glarus, Switzerland, a corporation ofSwitzerland N0 Drawing. Filed Apr. 30, 1962, Ser. No. 191,322 Claimspriority, applicatipnfgermany, Apr. 29, 1961,

6 Claims. 011260-2934 and valuable carboxylic acid esters of Z-hydroxymethyl piperidinium compounds which have a high spasmolytic acitivityand a surprisingly low toxicity.

Another object of the present invention is to provide a simple andelfective process of producing such new carboxylic acid esters ofZ-hydroxy methyl piperidinium compounds.

A further object of the present invention is to provide highly effectiveand well tolerated spasmolytic compositions containing, as active agent,such new carboxylic acid esters of 2-hydroxy methyl piperidiniumcompounds.

Still another object of the present invention is to provide a simple andeitective process of relaxing spastic conditions.

Other objects of the present invention and advantageous feasturesthereof will become apparent as the description proceeds.

In principle the new and valuable spasmolytic compounds according to thepresent invention are carboxylic acid esters of 2-hydroxy methylpiperidinium compounds of Formula I wherein R represents hydrogen,alkyl, aralkyl, cycloalkyl, aryl,

or heterocyclic radicals which may be substituted;

R represents hydrogen, alkyl, cycloalkyl, aralkyl, or aryl radicalswhich may be substituted;

R represents an aryl or a cycloalkyl radical which may be substituted;

R represents hydrogen, a hydroxyl group which may be esterified, orhalogen;

R represents an alkyl radical which may be substituted;

and

An indicates an anion.

The new compounds of Formula I are very effective spasmolytic agents ofa surprisingly/low toxicity. The LD i.e. the dose after administrationof which 50% of the test animals die, is, for instance, for the metho-Patented Mar. 15, 1966 sulfate of (l-methyl piperidyl-2)-methylbenzilate of Formula II N 0 CH3 SO4CH3 CH3 (II) which compound will bedesignated hereinafter as compound A on oral administration about 1.900mg./kg. of mouse body weight or respectively, about 3.700 ing/kg. of ratbody weight, and on subcutaneous administration 350 mg./kg. of mousebody weight or respectively, more than 2.000 mg./kg. of rat body Weight.The amount of Compound A needed for relaxation of the spastic conditionof the isolated surviving rat ileum caused by barium chloride is onlyone fiftieth of the required amount of papaverine. The spastic conditionof the isolated surviving rat ileum caused by acetylcholine is relaxedby Compound A in a concentration of 0.002 mg./ 1. Approximately, thesame results are obtained, for instance, by testing the benzilates of(l-n-butyl piperidyl-Z) -methanol methoiodide or (l-n-octylpiperidyl-2)-methanol methobromide.

These results could be confirmed for Compound A in clinicalinvestigations on humans. Side-elfects were not observed when thecompound was given orally, rectally, subcutaneously, or intramuscularly,respectively. In adults good spasmolytic efiects were observed afteroral or rectal administration of 20 mg. of Compound A or afterintramuscular administration of 1 mg. of Compound A. Cases of spasticbronchitis, of gastritis and/ or gastric ulcer, spastic colitis, spasmsof the gall-bladder and bileducts, renal colics, and others were treatedwith these new agents.

The new compounds of Formula I are prepared for instance, by thefollowing methods:

(A) A compound of Formula III wherein R R R and R have the same meaningas indicated in Formula I, is reacted, preferably in the presence of asolvent, with a compound of Formula IV 5 1 (IV) wherein R has the samemeaning as indicated in Formula I, and

X represents halogen or a sulfuric acid ester group.

(B) A compound of Formula V wherein R R R and R have the same meaning asindicated in Formula I, is reacted, if required, while heat- R CH Xwherein R has the same meaning as indicated in For- 5 mula I, and X hasthe same meaning as indicated in Formula IV.

(C) A compound of Formula VII N CH: Hal B, An

(I111; R (VII) wherein R R and An have the same meaning as indi cated inFormula I, and Hal represents halogen, is reacted with an acid ofFormula VIII I'M HOOC-(F-Rs R4 (VIII) wherein R R and R have the samemeaning as indicated in Formula I, in the presence of a compound capableof binding hydrogen halide or with a salt of such an acid of FormulaVIII, if desired, in presence of a solvent and preferably while heating.

(D) A compound of Formula IX N -CHzOH 12 An CH2 R1 (IX) wherein R R andAn have the same meaning as indicated in Formula I, is reacted with acompound of Formula X 2 -tr 0 R4 (X) wherein R R and R have the samemeaning as indicated in Formula I, and Y represents halogen or anesterified hydroxyl group,

0 either in the absence or m the presence of an inert organic solvent,preferably in the presence of a compound capable of binding the acidformed in the reaction, for instance, in the presence of a tertiaryamine, an alkali metal carbonate, an alkali metal bicarbonate, or thelike.

The anion present in the compound of Formula I resulting from proceedingaccording to one of the processes described herein above can be replacedby another suitable anion. For this purpose, for instance, a halide ofthe resulting quaternary ammonium compound may be reacted with a.suitable silver salt. In this manner compounds of Formula I can beproduced the preparation of which is difficult when following theprocesses described above.

The new compounds of Formula I contain at least one carbon atom which isasymmetrically substituted. Therefore, they can be obtained as racemicmixtures or in their optically active forms. In order to prepare saidcompounds in their optically active forms, optically active startingmaterials may be used in the processes described hereinabove. However,the new optically active compounds may also be prepared first in theirracemic form which is subsequently resolved to their optically activeisomers.

The following examples serve to illustrate the present inventionwithout, however, limiting the same to the contents of said examples.

Example 1 5 g. of (l-methyl piperidyl-2)-methyl benzilate are suspendedin 10 ml. of acetonitrile. A solution of 6.4 g. of methyliodide in 20ml. of acetonitrile is added thereto. The reaction mixture is allowed tostand at 3040 C. for 48 hours whereafter the solvent is distilled off ina vacuum. The residue is recrystallized from a mixture of acetone andpetroleum ether, whereby the methiodide of the starting material isobtained in a yield of 70% of the theoretical yield. Melting point:l30l32 C.

Example 2 A mixture of 5 g. of (l-methyl piperidyl-2)-methyl 'benzilate,7 g. of 'ethyliodide, and 30 ml. of dry acetone is refluxed for 6 hours.The residue obtained on distilling off the solvent is recrystallizedfrom a mixture of ethanol and petroleum ether. The resulting ethiodideof the starting material is obtained in a yield of 60% of thetheoretical yield. It melts at 151154 C.

Example 3 A mixture of 7.6 g. of dimethylsulfate and 15 ml. of acetoneis added to a solution of 10.2 g. of (l-methyl piperidyl-2)-methylbenzilate in 50 ml. of dry acetone. The reaction mixture is allowed tostand at 3040 C. for 2 days. The precipitated crystals are filtered ofl?and recrystallized from a mixture of acetone and ethanol while heatingand adding petroleum ether to the warm solution. The resultingmethosulfate is the compound A mentioned hereinabove. It melts at134-135 C. Yield: 92% of the theoretical yield.

Example 4 A solution of 5.7 g. of methyliodide in 10 ml. of acetone isadded to a solution of 7.6 g. of (l-n-butyl piperidyl-2)-methylbenzilate in ml. of dry acetone. The reaction mixture is allowed tostand at 3040 C. for 24 hours. Petroleum ether is added thereto untilthe mixture becomes turbid. The precipitate formed gradually afterstanding for 1 day to 2 days is filtered off by suction and isrecrystallized twice from a mixture of acetone and ethanol While heatingand adding petroleum ether to the warm solution. The resultingmethiodide of the starting material melts at l74175 C. The yield isabout 40% of the theoretical yield.

Example 5 A solution of 4.8 g. of methylbromide in 25 ml. of absoluteethanol is added to a solution of 11 g. of (l-noctyl piperidyl-2)-methylbenzilate in 40 ml. of dry acctone. After standing for 2 days at 30-40C., the solvents are removed by distillation in a vacuum. The residue isrecrystallized from a mixture of acetone and ethanol while heating andadding petroleum ether to the warm solution whereby the methobromide ofthe starting material which melts at l83l84 C. is obtained in a yield of58% of the theoretical yield.

Example 6 A solution of 5.7 g. of methyl iodide in 10 ml. of acetone isadded to a solution of 8.6 g. of (l-B-phenyl ethyl piperidyl-2)-methyl'benzilate in 25 ml. of dry acetone. After standing at 30-40" C. for 2days, the reaction mixture is freed of the solvent by distillation in avacuum. The residue is recrystallized from a mixture of acetone andether whereby the methiodide of the starting material is obtained in ayield of of the theoretical yield. Melting point: 173 C.

Example 7 6 g. of the (l-methyl pi peridyl-2)-methyl ester of diphenylacetic acid are dissolved in 20 ml. of absolute methanol. 15 g. of a 25%solution of methyl bromide in methanol are added thereto. The reactionmixture is allowed to stand at room temperature for one week. Afterconcentrating the reaction mixture by distillation in a Vacuum, theresidue is triturated with absolute ether. The resulting precipitate isfiltered off by suction and is recrystallized twice from a mixture ofabsolute ethanol and absolute ether. The methobromicle of the startingmaterial is obtained in a yield of 39% of the theoretical yield. Meltingpoint: 176-178 C.

Example 8 A mixture of 4.9 g. of ethyl bromide and ml. of acetone isadded to a solution of 5 g. of (l-methyl piperidyl-2)-methyl benzilatein 25 ml. of dry acetone. The reaction mixture is allowed to stand atroom temperature for 6 days. After concentrating the reaction mixture bydistillation in a vacuum, the residue is recrystallized first from amixture of acetone and petroleum ether and then from a mixture ofabsolute ethanol and petroleum ether. The ethobromide of the startingmaterial is thereby obtained in a yield of 46% of the theoretical yield.Melting point: l85-l87 C.

Example 9 A mixture of 10.2 g. of (l-methyl-piperidyl-2)-methylbenzilate, dissolved 50 ml. of acetone, and 25 ml. of a 25% solution ofmethylbromide in methanol is allowed to stand at room temperature forthree days. Petroleum ether is added thereto until the solution becomesturbid. The precipitate formed after standing overnight in an ice box,is filtered ofI, dried by exposure to the air, and recrystallized from amixture of absolute ethanol and petroleum ether. After drying byexposure to the air, the hydrate of the methobromide. of the startingmaterial is obtained in a yield of 66% of the theoretical yield. Meltingpoint: 108-109 C.

Example 10 3 g. of freshly prepared silver chloride are added to asolution of 4.8 g. of (l-methyl piperidyl-2)-methyl benzilate methiodidein 20 ml. of methanol. The mixture is shaken for 10 minutes and thenallowed to stand in the dark for 24 hours. After filtering otf theprecipitate by suction, the filtrate is freed of solvent by distillationin a vacuum. The residue is recrystallized from a mixture of acetone andethanol while heating and adding petroleum ether to the Warm solutionwhereby (l-methyl piperidyl- 2)-methyl benzilate methochloride, meltingat 1l5-l18 C. is obtained in a yield of 64% of the theoretical yield.

Example 11 Methyl bromide is passed at room temperature into a solutionof 5 g. of the ester of a-cyclohexyl phenyl glycolic acid and (l-methylpiperidyl-2)-methanol in 50 ml. of acetone until 12 g. of methylbromidehave been absorbed. Colorless crystals start to precipitate duringintroduction of the methylbromide. The reaction mixture is cooled in anice bath and the precipitated crystals are filtered off by suction.Thereby, the methobromide of the starting material is obtained in ayield of 63% of the theoretical yield. After recrystallization from amixture of acetone, ethanol, and petroleum ether, its melting point is197- 199 C.

Example 12 A mixture of 5.4 g. of 1-methyl-2-hydroxy methyl-piperidinemethiodide, 4.6 g. of diphenyl acetylchloride, 2 g. of triethylamine,and 100 ml. of dry dioxane is refluxed for three hours while stirring.After standing overnight, the solvent is decanted off and the residue isrecrystallized from a mixture of ethanol and petroleum ether. Thereby,the (l-methyl piperidyl-2)-methyl diphenylacetate methiodide is obtainedin a yield of 54% of the theoretical yield. Melting point: l65-1-68 C.

Example 13 4.9 g. of l-methyl-Z-chloro methyl piperidine methobromideand 5.3 g. of potassium benzilate are added to ml. of absolute ethanol.The mixture is refluxed for two hours while stirring and is thenfiltered while still hot. The filtrate is evaporated to dryness in avacuum and the resulting residue is recrystallized from a mixture ofacetone, ethanol, and petroleum ether whereby (l-methylpiperidyl-2)-methyl benzilate methobromide melting at -162 C. isobtained in a yield of 35% of the theoretical yield.

In place of the benzilic acid esters used in Examples 1 to 6, 8 and 9,the diphenyl acetic acid ester used in Example 7, and the a-cyclohexylphenyl glycolic acid ester used in Example 11, there may be employedother acid esters of l-alkyl-Z-hydroxy methyl piperidines l-phenyl loweralkyl-2-hydroxy methyl piperidines such as the corresponding esters witha-chloro diphenyl acetic acid or mandelic acid.

In place of the esters of the l-substituted-Z-hydroxy methyl piperidinesused in Examples 1 to 9, and 11, there may be employed the esters ofother l-substituted-Z-hydroxy methyl piperidines, for instance, theesters of other 1-alkyl-, l-phenyl lower alkyl, l-phenyl-Z-hydroxymethyl piperidines such as (l-benzyl piperidyl-2)-methyl benzilate,(l-ethyl piperidyl-2) methyl diphenyl acetate, (1- n-propyl-piperidyl-2)methyl mandelate, or the ester of a-chloro diphenyl acetic acid withl-methyl-Z-hydroxy methyl piperidine.

In place of diphenyl acetylchloride used as reactive acid derivative inExample 12 for esterifying l-methyl-Z-hydroxy methyl piperidinemethiodide, there may be employed other carboxylic acids as they arementioned hereinabove, or reactive derivatives of such acids, forinstance, their bromides, their anhydrides, their mixed anhydrides, forinstance, with alkyl carbonates, aryl carbonates or aralkyl carbonates.

In place of the l-methyl-Z-hydroxy methyl piperidine methiodide used forreaction with the acid chloride as described in Example 12, there may beemployed other quaternary l-substituted-Z-hydroxy methyl piperidiniumcompounds such as the methosulfate of l-methyl-Z-hydroxy methylpiperidine, the methochloride of l-methyl-2-hydroxy methyl piperidine,the methosulfate of l-ethyl-Z-hydroxy methyl piperidine, the ethosulfateof l-methyl-Z- hydroxy methyl piperidine.

Likewise, in place of l-methyl-Z-chloro methyl piperidine methobromideused for reaction with potassium benzilate as described in Example 13,there may be employed other quaternary l-substituted-Z-halogeno methylpiperidinium compounds such as l-methyl-Z-bromo methyl piperidinemethochloride, 1-ethyl-2-bromo methyl piperidine ethobromide,1-n-butyl-2-chloro methyl methochloride, 1- benzyl-Z-chloro methylmethobromide, 1-methyl-2-bromo methyl methobromide.

In all these reactions and with all these different starting materialsthe procedure is followed as it is described in the preceding examples.

In place of methyl and ethyl iodide, methyl and ethyl bromide, anddimethyl sulfate as used in the preceding examples, there may beemployed other quaternizing agents such as benzylbromide, diethylsulfate, other alkyl or aralkyl halogenides, such as iso-propyl iodide,n-butyl iodide.

Especially valuable spasmolytic compounds of low toxicity and highspasmolytic activity are the benzilic acid esters of 1-alkyl-2-hydroxymethyl piperidine methohalides or methosulfates.

The new esters of quaternary Z-hydroxy methyl piperidinium compounds areadministered orally, parenterally, or rectally. The preferred mode ofadministration is oral administration in the form of liquid or solidpreparations, such as tablets, pills, dragees, powders, capsules,solutions, emulsions, suspensions, dispersions, or in any other suitableform.

In the case of powders, fine uniform dispersion of the active compoundstogether with a usual carrier throughout said powder is of importance.Such a fine dispersion can be achieved by intimately mixing and millingthe active compound, for instance, in a ball mill with a solidpulverulent extending agent to the desired degree of fineness or byimpregnating the already milled, finely powdered, solid carrier with theactive compound in water or with a solution thereof in a suitableorganic solvent and then removing the water or solvent.

A fine dispersion of the active compound in water, sirup and the likecan also be brought about by emulsifying said compound with the aid of adispersing or emulsifying agent.

When preparing tablets, pills, powders, and the like solid preparations,the commonly used carriers and diluting agents, binders, and the liketableting adjuvants are employed, such as sugar, lactose, starch,pectin, bolus alba, stearic acid, magnesium stearate, and as bindersgelatin, gum arabic, methyl cellulose, carboxy ethyl cellulose, yeastextract, agar, tragacanth, and others. It is, of course, understood thatany of the tableting materials conventionally used in pharmaceuticalpractice can be employed provided there is no incompatibility with theactive compound.

Injectable preparations and suppositories for rectal administration mayalso be prepared.

Of course, many changes and variations in the starting materials andreactants, in the solvents used, in the reaction conditions,temperature, pH-value of the reaction mixture, duration, in the methodsof working up, isolating, and purifying the reaction products, and thelike may be made by those skilled in the art in accordance with theprinciples set forth herein and in the claims annexed hereto.

We claim:

1. The carboxylic acid ester of a quaternary Z-hydroxy methylpiperidinium compound of the formula 5 All (llHz R1 8 X is an acyl groupselected from the group consisting of the benziloyl, diphenyl acetyl,u-cyclohexyl phenyl glycoloyl, mandeloyl, and a-chloro diphenylacetyl p;

5 R is a member selected from the group consisting of hydrogen, alkyl of1 to 8 carbon atoms, phenyl, and phenyl lower alkyl;

R is lower alkyl; and

An is a member selected from the group consisting of halogen and thealkyl sulfate group SO R wherein R is lower alkyl.

2. The benzilic acid ester of l-methyl-Z-hydroxy methyl piperidiniummethosulfate of the formula References Cited by the Examiner UNITEDSTATES PATENTS 2,918,408 12/1959 Biel 260294.3 X 2,955,144 10/1960 Biel260-294.3 2,995,492 8/1961 Biel 260-2943 40 OTHER REFERENCES Biel etal.: Jour. Am. Chem. Soc., vol. 77, pages 2250- 225 6 (1955 Ryan et al.:Jour. Org. Chem., vol. 26, pages 15474550 (May 1961 NICHOLAS S. RIZZO,Primary Examiner.

1. THE CARBOXYLIC ACID ESTER OF A QUATERNARY 2-HYDROXY METHYLPIPERIDIMUM COMPOUND OF THE FORMULA
 2. THE BENZIULIC ACID ESTER OF1-METHYL-2-HYDROXY METHYL PIPERIDINIUM METHOSULFATE OF THE FORMULA